Complex biologically active molecules are challenging, expensive, and time-consuming to synthesize. Synthesizing chiral, non-racemic compounds with good enantio- and diastereoselectivity is even more challenging. An example of such a molecule is Compound 1:
This compound is a potent inhibitor of the hepatitis C virus (HCV) NS3/4A protease; it shows broad genotype activity and substantially improved in vitro profile compared to earlier generation HCV NS3/4A protease inhibitors. While synthetic routes to this compound exist, the existing methods typically require, for example, high catalyst loading, dilute reaction conditions, and the use of expensive starting materials. Of particular interest is the difluoromethylcyclopropyl amino acid substituent. Previous synthetic methods relied upon corrosive fluorination chemistry to synthesize this feature; however, such fluorination reactions are difficult to adapt for large-scale production of Compound 1.
There exists a need for new synthetic methods to construct enantioenriched difluoroalkylcyclopropyl amino acids and esters.